Unlike colorectal cancer, the recurrence of which frequently takes the form of hematogenous metastasis to the liver, locally advanced gastric carcinoma is most likely to develop into a state of peritoneal carcinomatosis
( 1 ). This is the basis for application of detection of free cancer cells in peritoneal washes by cytologic examination for assessing the likelihood of early recurrence. No patient with a positive cytologic result accompanied by serosal invasion survived for more than 3 years in two series
( 2,
3 ).
Intraperitoneal recurrence, on the other hand, was observed in several patients with negative cytologic results,indicating a lack of sensitivity for conventional cytologic examination
( 11 ).
Some investigators have attempted to improve on the sensitivity of cytologic examination by using immunohistochemistry. Among the patients who underwent potentially curative resection for gastric carcinoma with invasion to the serosa (T3), free cancer cells were in the range of 18% to 24%. In contrast, free cancer cells were detected in 33% of patients with curatively resected T3 tumors and in 38% of stage II-III gastric carcinomas through immunostaining of cytospins. Despite this clear advantage over conventional Papanicolaou staining, sensitivities achieved by these attempts still fell short of the sensitivity obtained with RT-PCR
( 4,
2 ).
Yasuhiro Kodera et al have recently applied the reverse transcriptase-polymerase chain reaction (RT-PCR) for sensitive detection of micrometastases in the peritoneal cavity, using carcinoembryonic antigen (CEA) as a target gene.
A decrease in the incidence of false-negative results with this technique has been shown, as evidenced by the fact that peritoneal carcinomatosis was seldom observed after several years of follow-up among patients negative for the examination. The problem with this system is that gene amplification and analysis of PCR products are so time-consuming that results could not be obtained during the operation. In addition, some false-positive results, which may be attributable to CEA-expressing noncancerous cells, have been encountered. CEA mRNA in these cases may be either illegitimately expressed by the noncancerous cells or expressed after induction by various cytokines. Because CEA mRNA levels are expected to be higher in cancer cells, a quantitative technique may be useful to distinguish between the presence of cancer cells and contamination with other CEA-producing cells.
With recent innovations in PCR technology, a new generation of thermal cycler (LightCycler; Roche Diagnostics, Mannheim, Germany) that combines continuous fluorescence monitoring of PCR and rapid-cycle PCR within glass capillaries has become available.
Quantitative measurement of CEA mRNA by the LightCycler with subsequent automatic data analysis can be completed well within 3 hours. Besides its use simply as a prognostic determinant, the results of RT-PCR can now be used to augment macroscopic findings for decisions concerning the application of treatment options in addition to surgical resection. For example, the current detection system can be used for selecting patients who are eligible for intraperitoneal chemotherapy or chemohyperthermia, which could be effective against microscopic dissemination while showing limited activity toward gross metastases
( 4,
5, 6,
7 ).
References
1) Benevolo M, Mottolese M, Cosimelli M,et al.Diagnostic and prognostic value of peritoneal immunocytology in gastric cancer.J Clin Oncol 1998;16:3406-3411.
2) Kodera Y, Yamamura Y, Shimizu Y,et al.Prognostic value of positive findings in patients with gastric carcinoma undergoing a potentially curative resection.J Surg Oncol 1999;72:60-65.
3) Bando E, Yonemura Y, Takeshita Y,et al.Intraoperative lavage for cytological examination in 1297 patients with gastric carcinoma.Am J Surg 1999;178:256-262.
4) Yasuhiro Kodera, Hayao Nakanishi, Seiji Ito, Yoshitaka Yamamura, Yukihide Kanemitsu, Yasuhiro Shimizu, Takashi Hirai, Kenzo Yasui, Tomoyuki Kato, Masae Tatematsu. Quantitative detection of disseminated free cancer cells in peritoneal washes with real-time reverse transcriptase-polymerase chain reaction. Annals of Surgery 2002;235:499-506.
5) Nakanishi H, Kodera Y, Torii A,et al.Detection of carcinoembryonic antigen-expressing free tumor cells in peritoneal washes from patients with gastric carcinoma by polymerase chain reaction.Jpn J Cancer Res 1997;88:687-692.
6) Kodera Y, Nakanishi H, Yamamura Y,et al.Prognostic value and clinical implications of disseminated cancer cells in the peritoneal cavity detected by reverse transcriptase-polymerase chain reaction and cytology.Int J Cancer 1998;79:429-433.
7) Nakanishi H, Kodera Y, Yamamura Y,et al.Rapid quantitative detection of carcinoembryonic antigen-expressing free tumor cells in the peritoneal cavity of gastric-cancer patients with real-time RT-PCR on the LightCycler.Int J Cancer 2000;89:411-417.
8) Goeminne J-C, Guillaume T, Symann M. Pitfalls in the detection of disseminated non-hematological tumor cells.Ann Oncol 2000;11:785-792.
9) Ko Y, Grunewald E, Totzke G,et al.High percentage of false-positive results of cytokeratin 19 RT-PCR in blood:A model for the analysis of illegitimate gene expression.Oncology 2000;59:81-88.
10) Ghossein RA, Bhattacharya S, Rosai J. Molecular detection of micrometastases and circular tumor cells in solid tumors.Clin Cancer Res 1999;5:1950-1960.
11) Abe S, Yoshimura H, Tabata H,et al.Curative resection of gastric cancer:Limitation of peritoneal lavage cytology in predicting the outcome.J Surg Oncol 1995;59:226-229.
